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Bicyclic compounds as ACC inhibitors and uses thereof

a technology of bicyclic compounds and inhibitors, which is applied in the direction of antibacterial agents, drug compositions, and metabolic disorders, can solve the problems of increasing the risk of type-2 diabetes (t2dm), stroke and coronary heart disease, and not providing the long-term health benefit needed for weight loss

Active Publication Date: 2018-06-05
NIMBUS DISCOVERY INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

These compounds provide a potential therapeutic approach for treating obesity and metabolic syndrome by simultaneously inhibiting fatty acid synthesis and stimulating oxidation, potentially leading to significant weight loss and improved insulin sensitivity without the side effects associated with central nervous system-targeting agents.

Problems solved by technology

Obesity also leads to social stigmatization and discrimination, which decreases quality of life dramatically.
Furthermore, about half of the obese population, and 25% of the general population, have metabolic syndrome, a condition associated with abdominal obesity, hypertension, increased plasma triglycerides, decreased HDL cholesterol, and insulin resistance, which increases the risk for type-2 diabetes (T2DM), stroke and coronary heart disease.
Diet and exercise, even when used in conjunction with the current pharmacotherapy, do not provide sustainable weight loss needed for long-term health benefit.
Unfortunately, poor efficacy and unappealing gastrointestinal side effects limit the use of orlistat.
Surgery can be effective but is limited to patients with extremely high body-bass indices (BMI) and the low throughput of surgery limits the impact of this modality to about 200 k patients per year.
However, the FDA has taken an unfavorable position against CNS-active agents, due to their modest efficacy and observed / potential side-effect profiles.

Method used

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  • Bicyclic compounds as ACC inhibitors and uses thereof
  • Bicyclic compounds as ACC inhibitors and uses thereof
  • Bicyclic compounds as ACC inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

of Compound 2-(7-(2-methoxyphenethyl)-3-methyl-2-(oxazol-2-yl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetic acid, I-33

[0349]

Synthesis of Compound 1.2

[0350]Into a 250-mL 3-necked round-bottom flask under nitrogen, was placed bis(propan-2-yl)amine (15.2 g, 150.21 mmol, 1.50 equiv) in THF (100 mL). The mixture was cooled to −40° C. and butyllithium (60 mL, 1.50 equiv, 2.5 mol / L) was added slowly stirred for 30 mins. The mixture was stirred at −40° C. for 30 min. Then, the above solution was added to a solution of 2-bromo-3-methylthiophene, compound 1.1 (17.7 g, 99.96 mmol, 1.00 equiv) in THF (100 mL) at −78° C. and stirred for 30 min. N,N-dimethylformamide (100 mL) was added at −78° C. Reaction was stirred for 1 hour at −78° C. The reaction was then quenched by the addition of 1 L of NH4Cl (aq.). and extracted with 3×500 mL of ethyl acetate. Organic layers were combined and washed with 2×1000 mL of brine. Organic layer was dried over anhydrous magnesium sulfate and solvents were under vac...

example 2

of Compound 2-(7-(2-methoxyphenethyl)-3-methyl-2-(oxazol-2-yl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acetamide, I-34

[0360]

[0361]A 25-mL 3-necked round-bottom flask kept under nitrogen, was charged with compound I-33 (40 mg, 0.08 mmol, 1.00 equiv), DCC (64 mg, 0.31 mmol, 3.73 equiv), CH2Cl2 (8 mL), NH4Cl (24.8 mg, 0.46 mmol, 5.57 equiv) and 4-dimethylaminopyridine (38 mg, 0.31 mmol, 3.74 equiv). Reaction was stirred overnight at 50° C. Upon completion, solvents were removed under reduced pressure. Crude was purified by preparative TLC and then by preparative HPLC to provide 1.9 mg (5%) of 2-(7-(2-methoxyphenethyl)-3-methyl-2-(oxazol-2-yl)-4-oxothieno[3,2-c]pyridin-5(4H)-yl)acet-amide, 1-34 as a white solid. LCMS (ES, m / z): 424 [M+H]+; 1H NMR (300 MHz, DMSO-d6): δ2.73-2.78 (t, 2H), 2.89-2.96 (m, 5H), 3.84 (s, 3H), 4.54 (s, 2H), 6.88-6.91 (t, 1H), 6.97-7.00 (dd, 2H), 7.19-7.24 (m, 3H), 7.44-7.47 (dd, 2H), 7.61 (s, 1H), 8.26 (s, 1H).

example 3

of 2-(4-(2-methoxyphenethyl)-2-(oxazol-2-yl)-5,7-dioxo-4,5-dihydrothiazolo[5,4-d]pyrimidin-6(7H)-yl)acetic acid I-35

[0362]

Synthesis of Compound 3.2

[0363]A 50-mL 3-necked round-bottom flask, was charged with compound 3.1 (200 mg, 1.16 mmol, 1.00 equiv), dichloromethane (10 mL) and triphosgene (115 mg, 0.39 mmol, 0.33 equiv). Triethylamine (352 mg, 3.48 mmol, 3.00 equiv) was the added dropwise while stirring at 0° C. The resulting solution was stirred for 1 h at 0° C. and used directly in the next step.

Synthesis of Compound 3.3

[0364]Into a 50-mL 3-necked round-bottom flask, was placed solution of compound 3.2 and tert-butyl 2-aminoacetate hydrochloride (194 mg, 1.16 mmol, 1.00 equiv). Reaction was stirred for 2 h at room temperature. Upon completion reaction was then quenched by the addition of 10 mL of NH4Cl(aq.) and extracted with 2×10 mL of dichloromethane. Organic layers were combined and concentrated under vacuum. The crude was purified using flash column chromatography to furnis...

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Abstract

The present invention provides compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

Description

CROSS REFERENCE OF THE APPLICATION[0001]This application is U.S. National Phase application under 35 U.S.C. § 371 of International Application PCT / US2014 / 37360, filed on May 8, 2014, which claims the benefit of U.S. Provisional Patent Application No. 61 / 821,824, filed on May 10, 2013.BACKGROUND OF THE INVENTION[0002]Obesity is a health crisis of epic proportions. The health burden of obesity, measured by quality-adjusted life-years lost per adult, has surpassed that of smoking to become the most serious, preventable cause of death. In the US, about 34% of adults have obesity, up from 31% in 1999 and about 15% in the years 1960 through 1980. Obesity increases the rate of mortality from all causes for both men and women at all ages and in all racial and ethnic groups. Obesity also leads to social stigmatization and discrimination, which decreases quality of life dramatically. The chronic diseases that result from obesity cost the US economy more than $150 billion in weight-related med...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D513/04C07D471/04C07D473/04C07D491/04C07D495/04C07D498/04A01N43/90C07D487/04
CPCC07D513/04A01N43/90C07D471/04C07D498/04C07D487/04C07D491/04C07D495/04C07D473/04A61P3/00A61P3/04A61P31/04A61P31/10A61P33/00A61P35/00A61P3/06A61P43/00A61P5/00
Inventor GREENWOOD, JEREMY ROBERTHARRIMAN, GERALDINE C.BORG, GEORGEMASSE, CRAIG E.
Owner NIMBUS DISCOVERY INC
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